BioPharma Encapsulated - Unveiling Spoke 6

Spoke 6 – RNA Drug Development

RNA technologies are emerging as new options for innovative treatments. Biotech companies and academic laboratories can rapidly develop RNA-based drugs that target and regulate gene expression. Synthetic mRNAs can increase or decrease the production of specific proteins, as other techniques such as RNA interference and antisense oligonucleotides (ASOs) influence the genetic messengers of proteins and other noncoding molecules.

Falling within the objectives to design, deliver, and manufacture gene therapy and RNA-based drugs, Spoke 6 lies as the Horizontal Spokes focused on developing the technologies needed to bring these products to fruition. Headed by the National Research Council of Italy (CNR), Spoke 6 aims to better understand the mechanisms that regulate RNA metabolism and decipher how the chemical modifications on RNA after its transcription may affect the interaction with treatments. Spoke 6 researchers also address possible side effects, the absorption capacity of ASOs, and the formation of unwanted reactions with other molecules in the body.

Spoke 6 faces these challenges through three complementary Work Packages (WPs) focusing on non-coding RNAs such as miRNAs, lncRNAs, circRNAs, and introns. These RNA elements are crucial in regulating gene expression and may represent important targets for future RNA-based therapies.

Led by the National Research Council of Italy (IGM- Institute of Molecular Genetics of Pavia), Spoke 6 affiliates include the University of Padua (UNIPD), University of Bologna (UNIBO), University of Siena (UNISI), Tor Vergata University of Rome (UniRoma2), University of Naples Federico II (UNINA), University of Bari Aldo Moro (UNIBA), Italian Institute of Technology (IIT), Ri.MED Foundation (Ri.MED), and Takis Biotech.

Spoke 6 seeks to develop new RNA-based therapeutic strategies using innovative third-generation sequencing, advanced imaging, and RNA editing strategies integrated with computational and artificial intelligence approaches.

Key activities include creating new bioinformatics tools and developing programmable RNA editing protocols that interfere with specific cellular processes related to genetic diseases or cancers. To achieve this, Spoke 6 researchers seek to leverage existing enzymes in cells that can induce changes from adenosine to inosine and from cytosine to uracil. Redirecting these enzymes allows for the correcting of genetic alterations or inducing the death of tumor cells. These approaches, acting on RNA, are safer than a genetic therapy based on DNA.

Another crucial goal is the implementation of direct RNA sequencing technologies (third-generation technologies), which are essential to clarify aspects related to non-coding RNAs (ncRNAs) and developing novel Cas-based Targeting Units for Specific Epigenetic Remodeling (TUSER) that can precisely and timely regulate the expression of target mammalian genes by rewriting their epigenetic landscape without introducing changes to the underlying DNA sequences.

The biochemical modifications of RNA, which enrich the simple RNA sequence by adding additional functional elements to the molecule, represent an emerging field called epitranscriptomics to develop drugs applicable to tumors, such as various forms of leukemia. Understanding how these modifications affect RNA interactions and functions is crucial, as it could have a significant impact on new RNA-based therapies or simply lead to understanding how to apply pharmaceuticals designed to target the biochemical pathways that operate RNA modifications.

Spoke 6 plans to develop an optical microscopy platform to visualize and quantify the efficacy of RNA-based therapies in living cells with cutting-edge tools. This platform will integrate different imaging techniques and use artificial intelligence to understand how to improve the efficacy of treatments and reduce their toxicity.

Foundation staff writer Ellen Jane Corcoran